ÐÓ°ÉÔ­´´

Why do people inhale the smoke of the burning dried leaves of the tobacco
plant despite numerous warnings from experts that it may kill them? The
answer seems to be, in part, that inhaling tobacco smoke is the fastest
and most efficient way yet discovered to get nicotine into the human brain
– and that nicotine is addictive. ÐÓ°ÉÔ­´´s have now established that nicotine
promotes addictive behaviour just as effectively as drugs traditionally
considered to be addictive and they have begun to discover how it does so.

Although tobacco smoke is a complex mixture of thousands of different
chemicals, it is nicotine that produces most of the immediate effects of
smoking on the body, and the addictive effects on brain and behaviour. But
it is substances in the smoke called ‘tar’ that are mainly responsible for
diseases such as lung cancer. So, the effects that smokers seek may be separable
from those that do the physical damage. We may be able to devise strategies
to limit the damage caused by smoking, and to help people to quit.

But why do scientists now believe tht nicotine is addictive? In the
early 1960s, most experts believed that smoking was a psychologically-based
habit that people indulged in to experience the taste and smell of the smoke,
to see the pretty patterns of the smoke-rings, and to gain oral satisfaction
in the psychoanalytic sense.

By the late 1970s, psychopharmacologists such as Steven Goldberg and
Roger Spealman, at Harvard University in Massachusetts, had demonstrated
that solutions of pure nicotine could serve as a reward – a so-called positive
reinforcer, in the language of behavioural psychology. This simply means
that people can learn or become ‘conditioned’ to find nicotine rewarding,
and so continue to seek it out. Experiments also showed that people altered
their smoking behaviour when researchers altered the amount of nicotine
delivered by their cigarettes, or gave them nicotine-like or nicotine-blocking
drugs. Animals can readily detect the characteristic subjective effects
of nicotine and can distinguish these from the effects of other drugs.

Other studies showed that tolerance developed to some, but not all,
of nicotine’s effects on behaviour. For example, doses of nicotine that
make non-smokers vomit fail to do so in regular smokers. Classical addictive
drugs such as heroin also produce tolerance. Such tolerance can persist
for several months after exposure to nicotine ends, and may be why people
who have given up smoking are likely to relapse. Further evidence that nicotine
is addictive is the fact that smokers experience withdrawal symptoms when
they give up.

By 1980 the evidence was so compelling that few researchers in the field
questioned the addictive nature of tobacco. But doctors and the public at
large have been slow to accept this finding because heroin tends to be seen
as a model for all addictions. Heroin addicts experience an immediate ‘high’
after taking the drug and suffer severe withdrawal symptoms if they stop
taking it. People assumed that the different effects of nicotine meant that
it was not really addictive. Tobacco is also unusual among abused substances
in that users may find some of the short-term psychological effects useful,
in altering mood or attention, say. Moreover, the symptoms of withdrawal
from tobacco are quite different from, and less severe than, withdrawal
from opiates. Yet addiction to drugs should not be defined merely by withdrawal
reactions. Central to all addiction, whether to a stimulant, a tranquilliser,
alcohol or nicotine, is the way the drug itself reinforces behaviour. That
is, people learn to find its use rewarding. The reduction of withdrawal
symptoms is one mechanism of reinforcement, but it is not the only one,
even for opiates. If the ability to produce striking withdrawal syndrome
is the main criterion, cocaine as well as nicotine would have to be considered
non-addictive. It is the strength, not the nature, of the reinforcing effect
that determines addictiveness.

All the same, it is important to understand the nature of the positive
reinforcing effect of nicotine that can keep people smoking. Several ideas
are currently under discussion. Jack Henningfield of the Addiction Research
Center in Baltimore, Maryland, has shown that nicotine can produce a state
of euphoria, a feeling of wellbeing that has no basis in reality, which
resembles the effects of classical addictive drugs. But the intensity of
this effect is probably not sufficient to explain why smoking is so reinforcing.

Other scientists believe that nicotine can enhance certain psychological
functions in ways that are actually important and useful for smokers. David
Warburton of the University of Reading suggests that nicotine can improve
concentration and enhance accuracy during the performance of boring tasks
that require sustained attention over long periods of time. There is also
evidence that nicotine may improve aspects of learning and memory and the
ability to process information rapidly.

Here, we need further research to distinguish more rigorously between
real benefits due to nicotine and the mere alleviation of declines in performance
caused by nicotine’s withdrawal. Nevertheless, the observations have encouraged
attempts to use nicotine to overcome some of the problems in learning and
memory in dementias such as Alzheimer’s disease.

Neil Grunberg of the Uniformed Services University of the Health Sciences
in Bethesda, Maryland, suggests that nicotine reduces the consumption of
sweet and high-calorie foods; this effect, like the increases in metabolic
rate that nicotine produces, may help people to keep their weight down.
David Balfour, of Ninewells Hospital in Dundee, believes that stress can
worsen the symptoms of nicotine withdrawal and that nicotine encourages
adaptive changes in the brain that facilitate coping with stress and anxiety.
For instance, ‘stress’ hormones produced by the adrenal glands may decrease
the brain’s sensitivity to nicotine, so it is possible that, through this
interaction, nicotine in turn helps people to deal with stress. It is not
yet clear, however, whether such hormonal effects influence addiction.

A final source of reinforcement that is widely discussed today is more
straightforward: people may continue to smoke merely to prevent nicotine
withdrawal syndrome. But although the reports of smokers suggest that this
is an important factor for many, especially heavy users, studies suggest
that the intensity of withdrawal symptoms is only one gauge of how likely
people are to continue smoking, and an imperfect one at that.

So researchers do not yet fully understand why using nicotine is positively
reinforcing, although all these different effects may play a role. Factors
that may be most important for one person may not be very significant for
others. Yet there may still be a common brain mechanism that ultimately
converts the different aspects of nicotine’s positive reinforcing effect
into drug-seeking behaviour, and much current research aims to identify
this elusive central mechanism.

Nicotine’s ability to somehow reward smokers may be at the core of tobacco
addiction, but other processes may be involved. Another kind of learning
may be involved beyond simple conditioning based on nicotine as a reward.
The idea here is that nicotine can act as a ‘discriminative stimulus’. Although
such a stimulus is not in itself rewarding, its presence acts as a ‘cue’
to perform a particular behaviour that has become linked to it through learning.
Stopping at traffic lights is a typical example of the control of behaviour
by such a stimulus. Drivers have learnt to associate a red light with stopping
the car. But not all discriminative stimuli are events in the environment.
Numerous experiments testify to the ability of nicotine to trigger continued
smoking by acting as a sort of internal ‘cue’. Nicotine could act in this
way because smokers can recognise the characteristic effects of dosing themselves
with nicotine. The sensations a smoker experiences can act as an internal
cue to maintain the habit.

Noxious nicotine

But nicotine also has powerful aversive effects at doses above those
normally obtained by smokers; these noxious effects may set an upper limit
to the amounts of nicotine to which smokers expose themselves. Heavy smokers
probably develop some tolerance to aversive effects which may explain why
many smokers gradually increase the number of cigarettes they smoke. Understanding
how this tolerance develops may help us to devise ways of reducing people’s
intake of tobacco.

So to understand nicotine addiction, we need to know how nicotine acts
on the brain to bring about positive reinforcement, ‘cueing’ and the aversive
effects that influence how much a person smokes. We need to understand,
too, the adaptive changes in the brain that underlie the nicotine withdrawal
syndrome.

Interest in nicotine dependency has increased rapidly over the past
decade with the discovery of receptors in the brain upon which nicotine
acts. In the mid-1970s, radioactively labelled nicotinic drugs were used
to identify where nicotine attaches to receptors on the outer membranes
of cells in the brain. The binding of any drug to receptors on cells can
lead to biochemical changes within cells, and set in train a series of events
which ultimately account for the drug’s action in the body. The trouble
is that not all the sites to which a drug binds are functioning receptors,
and researchers were hunting for those involved in addiction. Early studies
on nicotinic binding used alpha-bungarotoxin as the probe; this substance,
derived from a snake toxin, binds to receptors for nicotine on voluntary
skeletal muscles. But bungarotoxin works differently in the brain and binding
sites for the snake toxin there are probably not the receptors through which
nicotine exerts its addictive effects.

Studies then turned to the binding of radiolabelled nicotine. In 1980,
Avram Goldstein and his colleagues at Stanford University, in California,
demonstrated that nicotine binds tightly to certain nerve cells in rats’
brains. Subsequent studies from many laboratories have mapped the distribution
of these binding sites in different regions of the brain. Importantly, this
map is almost identical to the distribution of receptors for the neurotransmitter
acetylcholine. But are these binding sites the ones involved in addiction
to nicotine?

There is some evidence in favour of this idea. Workers in my laboratory
have found that several drugs that bind to acetylcholine receptors block
the binding of nicotine (implying that both the drugs and nicotine activate
the same receptors). Furthermore, trained rats identify these drugs as being
like nicotine. So the tight binding site for nicotine seems to be involved
in the ability of experienced subjects to recognise the nicotine’s effects
on the brain – and thus may be involved in the ‘cueing’ of smoking.

Other experiments have attempted to determine whether nicotine acts
in regions of the brain that are rich in binding sites. My colleagues and
I at the Institute of Psychiatry have found that the rats become more active
– a response to nicotine – after we infuse the drug directly into a region
of the forebrain containing cells that release the neurotransmitter dopamine.
This area of the brain is called the mesolimbic dopamine system.

Paul Clarke of the University of British Columbia in Vancouver, Canada,
has shown that damaging these dopamine-containing cells, by infusing a selective
neurotoxin, reduces this response to nicotine. Moreover, George Singer at
La Trobe University in Bundoora, Australia, has shown that similar lesions
reduce the tendency of rats to dose themselves with nicotine. So actions
on brain dopamine systems seem to play a crucial role in the genesis of
the effects of nicotine sought by tobacco users. This is a potentially very
important finding because the mesolimbic dopamine system plays a major role
in the reinforcement of behaviour by other addictive drugs such as amphetamine
and cocaine. It is also possible that nicotine may promote adaptive changes
in the mesolimbic dopamine system in ways that aid coping with stress.

Biochemical studies strongly support this conclusion by showing that
nerve terminals of the mesolimbic dopamine system carry nicotinic receptors.
Peter Rowell, of the University of Louisville, in Kentucky, and others have
shown that small concentrations of nicotine, like those in the blood of
cigarette smokers, can enhance the release of dopamine from the mesolimbic
system. Those nerve cells continue to respond to nicotine after repeated
doses and do not develop tolerance. This also suggests that the release
of dopamine may be relevant to the reinforcing action of nicotine. So nicotine
may act first at receptors for acetylcholine (the tight binding site for
nicotine); these receptors may then activate the dopamine system. Nicotine
can also act on other neurotransmitters and hormones, such as noradrenaline,
endogenous opiates and prolactin, and it can enhance the release of acetylcholine.
But so far these effects seem not to occur at doses of nicotine in the smoking
range, or have not been directly linked with addictive behaviours.

The question now posed is whether the actions of nicotine at a single
binding site can account for all its behavioural and addictive effects.
The best answer we can give at the moment is, probably not. Even the involvement
of dopamine, which is known to be involved in other addictions and rewarded
behaviours, provides only a partial explanation of nicotine’s reinforcing
effect. It is also possible that another neurotransmitter, 5-hydroxytryptamine,
acts on 5-HT3 receptors to enhance the effect of nicotine on the dopamine
system. Furthermore, recent studies at the molecular level indicate that
there are several slightly different types of central nicotinic receptors.

Several laboratories are now seeking evidence on the functional significance
of these various types of central nicotinic receptors but it is too early
to draw conclusions. However, some researchers believe that nicotine probably
acts upon a diverse range of receptors to produce its wide spectrum of behavioural
effects. If this proves to be true, it may become possible to synthesise
new compounds that can mimic some of the effects of nicotine but which do
not share its undesirable effects. It might also be possible to design drugs
that block nicotine’s central, addictive effects without interfering with
its effects on other parts of the nervous system. This may open a route
to the design of more sophisticated means for dealing with the pharmacological
component of tobacco addiction. We might also be able to design drugs that
possess some of the potentially useful properties of nicotine without peripheral
and other side-effects, and perhaps without the same potential for addiction.
The most obvious possibility is to capitalise on nicotine’s beneficial effects
on learning and memory, by developing agents that minimise memory deficits
in senile dementias but do not affect the heart and circulation, or produce
nausea and vomiting.

Dr Ian Stolerman is at the Institute of Psychiatry in London.

Further reading The biology of nicotine dependence, J Marsh (ed), Ciba
Foundation, 1990. Nicotine psychopharmacology: molecular, cellular and behavioural
aspects, S Wonnacott, MAH Russell, IP Stolerman (eds), Oxford University
Press, 1990.